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activated, the resulting lung damage can generate more tissue Adequate activation > appropriate immune response >
debris that constitutes DAMPs, which will tend to further > pathogen eradication & triggering of resolution phase
inflammation. If that reinforcing cycle becomes sufficiently chemistry > resolution
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active, the patient can move into cytokine storm, ARDS,
septic shock, cardiac or renal damage and other factors Excessive activation > epithelial & endothelial tissue
associated with fatality risk in COVID-19. 10 damage > DAMPs/PAMPs > further inflammatory
The immune system’s process of responding to a cytokine generation > increased influx of immune
pathogen includes effects that are inherently inflammatory. elements (neutrophils, macrophages, etc.) > more
It’s important to recognize that “inflammation” is not a damage > loop (failure of resolution)
single process that simply goes up and down, but an
orchestration of interconnected processes with a So, any clinical intervention that involves supporting
choreography that normally includes the chemistry of anti-pathogenic immune responses needs to be introduced
activation—as well as resolution—with many factors and sustained with discernment, as excessive inflammatory
involved in regulatory processes that determine to the activation or a skewing toward oxidative stress risks
total outcome. Any and all methods of stimulating, driving the patient to express a potentially excessive
activating and enhancing the immune system’s ability to inflammatory response. For every patient, there is a
recognize and kill any pathogen, including the moving, multifactorial equation that determines the status
SARS-CoV-2 virus, will of necessity involve the immune of their interconnected systems such as the inflammatory
system generating a cellular and biochemical response, process specifically (itself multifactorial), the effectiveness
not limited to but including appropriate production of of resolution chemistry and other modulating mechanisms,
inflammatory cytokines. The immune system is a deeply and their overall host defense response generally – all
interconnected system of feedback loops, balances against the backdrop of any co-morbidities or pre-existing
(protease/anti-protease; oxidant/anti-oxidant) and conditions/disease. This set of variables needs to be
compensatory processes (inflammation/resolution of addressed with discernment when crafting approaches in
inflammation). There is no escaping this effect. the clinical setting. For some patients, concerns about

Figure 4. The patient’s baseline level of pulmonary and systemic inflammation may in some cases impact their
fatality risk. In A, the patient’s baseline level of inflammation at onset of infection is modest. As the immune
response to the virus evolves, inflammatory cytokines are generated, moving the patient further up the vertical axis.
However, the patient’s biology can accommodate this increase, as the incremental increase in inflammation is far
from that which might risk moving the patient into manifesting ARDS, septic shock, heart or kidney failure, etc. In
B, the patient’s baseline level of inflammation at onset of infection is higher. The same incremental additional
inflammation associated with the immune system’s choreography of responding to the virus moves the patient
correspondingly further up the vertical axis, moving the patient closer to the threshold of manifesting ARDS or
other fatality risks. It’s noteworthy that, in some cases, inflammation may rapidly escalate from a low baseline to an
excessively vigorous inflammatory response that puts the patient in jeopardy, for a host of reasons both known and
unknown. So, a low starting inflammatory baseline may not be decisively protective. Nonetheless, moving the
patient down the vertical axis, so that the crescendo of the inflammatory process inherent in killing virus doesn’t
bring them across their threshold of fatality risk, is a worthy clinical goal that may improve the patient’s outcome.

10 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19